Electrophysiology and pathology evaluation of the Yucatan pig as a non-rodent animal model for regulatory and mechanistic toxicology studies

Six male and six female Yucatan pigs were utilized to investigate the feasibility of this species as a non-rodent model for routine regulatory and mechanistic toxicology studies. This study evaluated disease surveillance and computerized electrophysiology, along with possible gross and micropathology changes. Two pigs were used as sentinel animals to evaluate the microbiological status of the vendor upon arrival; the other pigs were maintained as biomonitors and to provide baseline clinical chemistry, urinalysis, pathology and electrophysiology data. The electrophysiology tests conducted included electrocardiography (ECG), electroretinography (ERG) and quantitative electroencephalography (qEEG), which achieved consistent baseline values with acceptable intrasubject variation. Tissue cholinesterase and histochemical staining were done to determine their suitability for testing cholinesterase compounds. Evaluation of the serum chemistry profile demonstrated increased CPK and LDH, which was likely associated with slight haemolysis or minor subclinical muscle stress during handling. There were no additional clinical chemistry changes or findings in haematology, urinalysis parameters or gross pathology. Micropathology found an absence of background lesions which would interfere with routine toxicology studies, except for a mild rhinitis. The aetiological agent was identified by electron microscopy as being consistent with inclusion body rhinitis of swine, previously unreported in miniature swine. This would most notably interfere with inhalation studies. The anatomical and physiological similarities of the Yucatan pig, along with its ability to accept the performance of electrophysiology tests allow this species to be considered as a suitable model for organ system testing in toxicology studies.     

Resorbable plate osteosynthesis of dislocated or pathological mandibular fractures: a prospective clinical trial of two amorphous L-/DL-lactide copolymer 2-mm miniplate systems

The purpose of this study was to evaluate the indication for resorbable miniplates in traumatic and pathological mandibular fractures. Two resorbable miniplate systems, the 2.0-mm MacroSorb (Macropore, San Diego, Calif.) and the PolyMax (Synthes, Oberdorf, Switzerland), were prospectively used in 24 mandibular osteosyntheses. Made from amorphous 70:30 poly-L/DL-lactide, amorphous copolymer plates have not yet been evaluated for mandibular osteosyntheses. The main advantage of the amorphous copolymer-structure is continuous hydrolysis through water penetration into the implant body during the first 6 months. Hydrolysis breaks the copolymer chains into smaller particles that later become degraded through phagocytotic cells. Twelve patients, aged 13 to 83 years, were treated after providing informed consent. Fourteen dentate patients with moderately dislocated traumatic fractures and two edentulous atrophic and dislocated traumatic mandibular fractures were treated. Two patients with pathological fractures due to osteomyelitis received osteosynthesis after sequestrectomy. Histological specimens of the plates, screws, and surrounding soft tissues were taken after 3, 6, 9, and 12 months in secondary dental implant operations. A total of 22 osteosyntheses healed well without clinical or radiological signs of dislocation, insufficient or excess formation of callus, pseudarthrosis, or plate fracture. The follow-up time ranged from 4 to 22 months. One patient with osteomyelitis worsened because of widespread osseous infection, and one with atrophic fracture developed a bland fibrous pseudarthrosis. The histological specimens showed a moderate inflammatory foreign body reaction. No sinuous drainage or clinically apparent inflammation occurred. The presented osteosynthesis systems showed reliable stability for mandibular osteosynthesis in cooperative patients; however, two treatment failures occurred (8 percent). Disadvantages of the resorbable osteosyntheses were costs, greater diameter, screw breakage, and the need to place the screws vertically to the plate. The use of resorbable osteosyntheses in dislocated fractures should be further evaluated in controlled studies.     

Metastatic sweat gland adenocarcinoma: A clinico-pathological dilemma

Background  

Sweat gland adenocarcinoma is a rare malignancy with high metastatic potential seen more commonly in later years of life. Scalp is the most common site of occurrence and it usually spreads to lymph nodes. Liver, lung and bones are the distant sites of metastasis with fatal results. The differentiation between apocrine and eccrine metastatic sweat gland carcinoma is often difficult. The criteria's are inadequate to be of any practical utility.     

OPA1 (dys)functions

Mitochondrial morphology varies according to cell type and cellular context from an interconnected filamentous network to isolated dots. This morphological plasticity depends on mitochondrial dynamics, a balance between antagonistic forces of fission and fusion. DRP1 and FIS1 control mitochondrial outer membrane fission and Mitofusins its fusion. This review focuses on OPA1, one of the few known actors of inner membrane dynamics, whose mutations provoke an optic neuropathy. Since its first identification in 2000 the characterization of the functions of OPA1 has made rapid progress thus providing numerous clues to unravel the pathogenetic mechanisms of ADOA-1.     

Determination of Sample Sizes for Demonstrating Efficacy of Radiation Countermeasures

Summary .  In response to the ever increasing threat of radiological and nuclear terrorism, active development of nontoxic new drugs and other countermeasures to protect against and/or mitigate adverse health effects of radiation is ongoing. Although the classical LD₅₀ study used for many decades as a first step in preclinical toxicity testing of new drugs has been largely replaced by experiments that use fewer animals, the need to evaluate the radioprotective efficacy of new drugs necessitates the conduct of traditional LD₅₀ comparative studies ( FDA, 2002 ,  Federal Register   67, 37988–37998). There is, however, no readily available method to determine the number of animals needed for establishing efficacy in these comparative potency studies. This article presents a sample-size formula based on Student's  t  for comparative potency testing. It is motivated by the U.S. Food and Drug Administration's (FDA's) requirements for robust efficacy data in the testing of response modifiers in total body irradiation experiments where human studies are not ethical or feasible. Monte Carlo simulation demonstrated the formula's performance for Student's  t , Wald, and likelihood ratio tests in both logistic and probit models. Importantly, the results showed clear potential for justifying the use of substantially fewer animals than are customarily used in these studies. The present article may thus initiate a dialogue among researchers who use animals for radioprotection survival studies, institutional animal care and use committees, and drug regulatory bodies to reach a consensus on the number of animals needed to achieve statistically robust results for demonstrating efficacy of radioprotective drugs.